Pulmonary function testing

Summary

Pulmonary function tests typically consist of 3 sections.

• Spirometry evaluates air movement and measures key metrics such as FVC and FEV₁.  These values define the obstructive pattern (FEV₁/FVC <0.7).  Spirometry is often performed before and after an acute bronchodilator, which differentiates between reversible (eg, asthma) and irreversible (eg, emphysema) obstruction.
• Plethysmography (and other techniques) measures the lung volumes that cannot be assessed via spirometry, namely total lung capacity (TLC), functional residual capacity (FRC), or residual volume (RV).  These values define the restrictive pattern (TLC, FRC, or RV <80%). 
• Diffusing capacity of the lungs for carbon monoxide (DLCO) evaluates gas transfer from the alveolar airspace into the capillary blood.  This can differentiate between pathologies in which the alveolar membrane is normal (eg, obstructive:  chronic bronchitis; restrictive:  chest wall deformity) or diseased (eg, obstructive:  emphysema; restrictive:  interstitial lung disease). 

Definitions

During pulmonary function testing, patients blow through tubing connected to a flowmeter.  This produces a graph of exhaled volume against time.  The graph is often presented as an idealized spirogram, showing tidal breathing followed by a forced vital maneuver ( figure 1).  From the spirogram, 4 lung volumes and 4 capacities can be defined.

Lung volumes are fundamental units (ie, they cannot be expressed in terms of each other):

• Tidal volume (TV):  the volume of a normal, quiet breath.
• Inspiratory reserve volume (IRV):  the volume that can be further inspired after normal tidal inhalation.
• Expiratory reserve volume (ERV):  the volume that can be further expired after normal tidal exhalation.
• Residual volume (RV):  the volume remaining in the lungs after maximal expiration. 

Lung capacities are the sum of ≥2 lung volumes:

• Total lung capacity (TLC = RV + ERV + TV + IRV):  the maximum amount of air that can be held in the lungs.  It is the sum of all lung volumes.
• Vital capacity (VC = ERV + TV + IRV):  the maximum amount of air that can be inspired or expired.  It is the sum of all lung volumes, excluding RV. 
• Inspiratory capacity (IC = TV + IRV):  the amount of air that can be inspired after tidal exhalation.
• Functional residual capacity (FRC = RV + ERV):  the amount of air that remains in the lungs after tidal exhalation.  This is also the resting, effortless volume of the respiratory system, corresponding to the equilibrium between the elastic collapsing force of the lung tissue and the elastic expanding force of the chest wall.

VC is considered the master indicator of lung function because it represents the total amount of moveable air.  It is helpful to think of VC as the difference between TLC and RV (VC = TLC − RV).  A reduced VC can be caused by:

• A decrease in TLC due to restrictive conditions (eg, interstitial lung disease [ILD])
• An increase in RV due to obstructive conditions (eg, chronic obstructive pulmonary disease [COPD])

Lung volumes reflect these different conditions ( figure 2).

Spirometry relies on air movement through a tube, so it only measures volumes that can be actively inhaled or exhaled.  Therefore, spirometry cannot measure RV or the capacities constructed from it (ie, FRC and TLC).  These 3 values (RV, FRC, and TLC) require specialized equipment.

There is often confusion between the clinical and technical usage of the term "volume."  In clinical settings, the expression "lung volume testing" is used even when measuring capacities (rather than volumes).

Components of pulmonary function tests

Pulmonary function test (PFTs) refer to a group of studies generally consisting of 3 parts:

• Air movement (ie, spirometry)
• Lung volumes (ie, plethysmography)
• Gas transfer (ie, diffusion capacity)

An order for "full PFTs" generally refers to all 3 components performed as a set.

Spirometry measures air movement through a tube.  Therefore, it captures all volumes and capacities that do not depend on RV.  Clinically, the 3 values of greatest interest are:

• FVC
• FEV₁
• FEV₁/FVC ratio

Healthy individuals empty ~80% of their lungs in the first second (ie, normal FEV₁/FVC ≈ 0.8).  Early flow is fastest because fully inflated lungs have the highest elastic recoil (ie, because the tissue is stretched taut) and lowest airway resistance (ie, because the bronchi are expanded to their largest diameter).  Conditions that decrease elastic recoil (eg, emphysema) or increase airway resistance (eg, asthma) selectively impact early airflow, resulting in a low FEV₁/FVC ratio (eg, obstruction is defined as FEV₁/FVC <0.7).

Lung emptying is effort independent because expiratory flow is determined entirely by intrinsic elastic recoil of the respiratory system (eg, decreased in emphysema)—a property cannot be voluntarily altered.  This can be verified firsthand by comparing passive against very forceful exhalation:  The emptying is identical.

Plethysmography operates on the Boyle gas law (P₁·V₁ = P₂·V₂).  It uses an airtight body box that calculates the absolute volume from the absolute pressure.  Plethysmography captures the 3 quantities that depend on RV (often called static volumes because air movement is not required):

• TLC
• FRC
• RV

Lung volume measurement is always needed to confirm a restrictive pattern (defined as TLC, FRC, or RV <80% predicted).

Gas transfer is assessed using the DLCO.  Because CO equilibrates immediately across the alveolar membrane (ie, extremely high hemoglobin affinity), the difference between inhaled (known) versus exhaled (measured) CO reflects the rate of diffusion, indicating the health of the airspace-capillary interface.

A variety of other studies yield further insight into respiratory system physiology.  These expanded or auxiliary PFTs include:

• Peak expiratory flow rate (PEFR):  Unlike overall lung emptying, instantaneous peak flow is effort dependent.  Therefore, PEFR serves as an early indicator of impending respiratory muscle fatigue during obstructive lung disease exacerbations (eg, asthma yellow or red zone). 
• Provocation testing:  Bronchoconstriction sometimes needs to be provoked (eg, methacholine) in order to diagnose intermittent asthma.  Methacholine is a muscarinic agonist that targets smooth muscle M3 receptors to directly constrict the airways.  A high susceptibility to methacholine (ie, minuscule dose needed to induce ≥20% reduction in FEV1) has a moderate positive predictive value for asthma; conversely, a negative test has strong negative predictive value and reliably excludes asthma.
• 6-minute walk distance (6MWD) (ie, pulmonary stress test):  Patient walks as far as possible in 6 minutes while wearing a pulse oximeter to monitor desaturation and supplemental oxygen needs.  The distance has strong prognostic value across a variety of chronic lung diseases.
• Respiratory muscle strength:  A variety of tests can assess respiratory muscle function, including negative inspiratory force (which measures instantaneous diaphragm strength) and eucapnic maximal voluntary ventilation (which measures endurance). 

Stepwise approach

A standard approach to PFT interpretation is outlined ( figure 3).  The study is assumed to be valid (eg, good patient cooperation and reproducibility).

During the PFT, air flow and lung volumes are measured simultaneously, allowing a flow-volume loop to be constructed.  The shape of the flow-volume loop can offer quick visual clues toward a diagnosis ( figure 4):

• Normal shape but shrunken indicates restrictive lung disease (eg, idiopathic pulmonary fibrosis).
• Expiratory scalloping indicates small airway obstruction (eg, asthma, COPD).
• Expiratory flattening indicates variable intrathoracic obstruction (eg, tracheobronchomalacia).
• Inspiratory flattening indicates variable extrathoracic obstruction (eg, vocal cord dysfunction).
• Biphasic flattening indicates fixed obstruction (eg, tracheal stenosis or tumor).

Spirometry (and lung volumes) are used to classify lung conditions into an obstructive or restrictive pattern:

• Normal:  If FEV₁ and FVC are normal (ie, ≥80%) and FEV₁/FVC ≥0.7, the patient's symptoms may be due to an intermittent respiratory process; methacholine challenge may be needed to provoke asthmatic obstruction.
• Obstructive:  Obstruction is present when FEV₁ and/or FVC are reduced (eg, <80%) and FEV₁/FVC <0.7.  If this is present, the next step is to assess reversibility based on pre- and post-bronchodilator testing (eg, albuterol). 
• Restrictive:  Restriction is suspected when FEV₁ and/or FVC are reduced (eg, <80%) despite FEV₁/FVC ≥0.7.  However, confirmation with lung volume plethysmography is required.  Restriction is defined by low lung volumes (ie, TLC, FRC, and/or RV <80%). 

Obstructive and restrictive lung diseases are often assigned a grade (not for memorization).

• Obstruction is graded by FEV₁ to best reflect early expiratory flow.  It ranges from mild (ie, ≥80%, GOLD stage 1 COPD) to very severe (ie, <35%, GOLD stage 4 COPD).
• Restriction is graded by TLC to best reflect lung volume.  It ranges from mild (ie, ≥80%) to severe (ie, <50%).

DLCO can further clarify the etiology of obstructive and restrictive conditions:

• Obstructive:  DLCO is decreased when the alveolar surface area is destroyed (eg, emphysema), relatively preserved when the alveoli are intact (eg, chronic bronchitis), or sometimes increased when there is bronchial hyperemia (eg, asthma).
• Restrictive:  DLCO can be low with intrinsic restriction (eg, ILD) or normal with extrinsic restriction (eg, neuromuscular weakness).

DLCO also correlates with hypoxemia and supplemental oxygen requirements.

Obstructive pattern

An obstructive ventilatory defect is defined as spirometry showing FEV₁/FVC <0.7 prior to a bronchodilator.

Obstruction can be reversible or irreversible.  These 2 are distinguished by the response to a short-acting bronchodilator (eg, albuterol):

• Reversible (ie, asthma):  FEV₁/FVC <0.7 before a bronchodilator but improves to >0.7 afterward.
• Irreversible (eg, COPD):  FEV₁/FVC <0.7 before and after a bronchodilator

A "positive bronchodilator response" (defined as an improvement in FEV₁ or FVC by ≥10% after administration of albuterol) is a related but distinct concept.  Some patients have a positive bronchodilator response but persistent obstruction (eg, post-bronchodilator FEV₁/FVC still <0.7).  This situation frequently arises in asthma—COPD overlap, which is characterized by an irreversible obstruction with a bronchospastic component.

In obstructive conditions, lung volumes can show hyperinflation and/or air trapping ( figure 5).

• Hyperinflation refers to overall alveolar enlargement (eg, due to loss of elastic tissue and septations).  It is reflected by an elevated TLC and/or FRC (>120%).  It correlates with a "barrel chest" appearance and diaphragm flattening on chest x-ray. 
• Air trapping refers to retention of volume due to expiratory closure of small airways (eg, loss of radial elastic support).  It is reflected by an elevated RV (>120%) and/or an RV/TLC.  An isolated increase in RV, a sensitive indicator of small airway collapse and early air trapping, is possibly the first detectable sign of COPD on PFT.

Restrictive pattern

A restrictive ventilatory defect is defined as decreased lung volumes (TLC, FRC, or RV <80%).

Restriction can be intrinsic or extrinsic.  They are distinguished by DLCO:

• Intrinsic (low DLCO):  Restriction originates from stiff lung parenchyma (eg, fibrotic ILD).  DLCO is reduced due to thickening of the alveolar basement membrane.  Subsequent work-up typically focuses on evaluating the lung interstitium (eg, high resolution CT scan of the chest).  Note that spirometry can show FEV₁/FVC ≥0.7 (and often higher) because fibrotic lung disease is associated with increased elastic recoil, which can cause high early airflow.
• Extrinsic (normal DLCO):  Restriction originates from extrapulmonary issues such as neuromuscular disease (eg, myasthenia gravis) or chest wall deformity (eg, severe kyphosis).  DLCO is preserved because the alveolar membrane is intact.  Subsequent work-up typically focuses on evaluating for neuromuscular weakness (eg, diaphragm sniff fluoroscopy, maximal voluntary ventilation). 

Isolated DLCO reduction

An isolated reduction in DLCO (ie, low DLCO but normal spirometry and lung volumes), called pulmonary vascular pattern, reflects a dissociation between gas transfer and respiratory mechanics; it usually indicates a problem with pulmonary blood flow.

• Alveolar perfusion is impaired (ie, low DLCO), but
• Airway and parenchymal function is intact (ie, normal spirometry and lung volumes). 

This situation is analogous to hypoxemia with a clear chest x-ray.  Common etiologies include pulmonary hypertension and pulmonary thromboembolism.  Hepatopulmonary syndrome (diffuse pulmonary capillary vasodilation seen in advanced cirrhosis) also produces a similar picture due to the increased diffusion distance and rapid transit of erythrocytes.

Other etiologies of an isolated low DLCO include:

• Anemia:  DLCO is reduced due to reduced hemoglobin carrying capacity.  DLCO is typically normalized (ie, corrected) for hemoglobin.
• Early ILD or left heart failure:  Very minimal amounts of interstitial thickening (eg, fibrosis, pulmonary edema fluid) can impair diffusion before they cause abnormalities in spirometry, lung volumes, or even visible infiltrates on chest imaging.
• Mixed obstructive and restrictive disease:  Obstruction (low FEV₁/FVC ratio, high lung volumes) and restriction (high FEV₁/FVC ratio, low lung volumes) have opposing effects that can result in pseudonormalized spirometry and volumes.  However, DLCO can be greatly reduced by the "double hit."

Normative conditions

The main impact of aging on PFT is a gradual elevation of RV ( figure 6).  Aging is associated with a progressive degradation of lung elastin.  Loss of elastic airway tethering fibers allows for easy expiratory closure and air trapping.  Therefore, RV progressively rises, roughly doubling between age 30 and 70.  This produces a concomitant reduction in VC.  In this way, emphysema is often likened to a highly accelerated form of lung aging.  However, PFT values are normalized (ie, expressed as a percent of predicted) for age and height.  Therefore, even though RV increases (and VC decreases), PFT values remain in the normal range within the aging cohort.

The primary impact of obesity on PFT is a reduced FRC due to the weight of adipose tissue around the thorax and abdomen.  If plethysmographic lung volumes are unavailable (ie, only spirometry is available), a low ERV can be a surrogate for decreased FRC.  Despite this low-resting lung volume, the inspiratory muscles can compensate and expand the lungs fully against the excess weigh; therefore, TLC is typically preserved.  A true restrictive pattern (ie, TLC <80%) is usually not seen until obesity becomes extreme (eg, BMI is ≥60 kg/m²), at which point the diaphragm cannot counter the increased load.

The main impact of pregnancy of PFT is reduced FRC due to upward displacement of the lungs by the gravid uterus.  Progesterone stimulates a respiratory drive to increase RV and respiratory frequency, resulting in a higher minute ventilation and slight respiratory alkalosis.  However, spirometry and other lung volumes are generally unaffected.  DLCO is slightly elevated due to increased circulating blood volume and cardiac output.